3-ethylenedioxy-4,4-seco-gonene-5-ones

ABSTRACT

3-ETHYLENEDIOXY-13B-R-4,5-SECO-GONENE-5-ONES HAVING A KETONE OR A B-HYDROXYL GROUP IN THE 17 POSITION, WHERE R IS ALKYL HAVING 1 TO 4 CARBON ATOMS, WHICH ARE USEFUL AS INTERMEDIATES IN THE PRODUCTION OF KNOWN STEROIDS HAVING USEFUL PHYSIOLOGICAL PROPERTIES.

Patented Apr. 16, 1974 Jacques Prost-Marechal, Paris, and GeorgesTomasik, Rosny-sous-Bois, France, assignors to Roussel-UCLAF, Paris,France 5 No Drawing. Original application Jan. 23, 1969, Ser. No.

793,554, now Patent No. 3,646,151. Divided and this k t 1 applicationAug. 19, 1971, Ser. No. 173,306 e e Claims priority, application France,Jan. 26, 1968,

B-ETHYLENEDIOXY-4,4-SECO-GONENE--ONES 13,763 wherein R represents analkyl having 1 to 4 carbon atoms Int, Cl, (107d 13/04 and A represents amember selected from the group con- U.S. Cl. 260-3403 2 Claims sistingof 0H ABSTRACT OF THE DISCLOSURE o and c=0 3 ethylenedioxy 13p R 4,5seco-gonene-S-ones having a ketone or a p-hydroxyl group i h 17 i i bythe action of a basic isomenzation agent, followed by where R is alkylhaving 1 to 4 carbon atoms, which are the achon of an acid, OXidiZlIlgthe resultant 3-ketal useful as intermediates in the production of knownof a 1 R $ew-A9uD-80Imm-3,5-di0ne 0f the steroids having usefulphysiological properties. 20 formula REFERENCE TO A PRIOR APPLICATIONThis application is a division of our copending United States patentapplication Ser. No. 793,554, filed Jan. 23, 1969, now Pat. No.3,646,151.

OBJECTS OF THE INVENTION An object of the invention is the obtention ofnovel hydroxylated tricyclic compounds useful as intermediates wherein Rand A have the above-assigned meanings, by

in the production of known steroids the action of a gas containingoxygen, in a basic media, Another object of the present invention is theobtention (c) shhlectmg the resultant an llh'hydro' of 13 4 5 9 3 5 ofthe formula peroxy-13,8-R-4,5-seco-A -gonene-3,5-d1one of the formula RR Ho L H00 .A

40 \O ketal 0 wherein R represents an alkyl having 1 to 4 carbon atoms'f R and A f the ehove'esstghed meanings, to and A represents a. memberselected from the group conthe aettoh of a reducing agent hydrolyzlhgthe sisting of sultant 3-keta1 of an 1lp-hydroxy-13fi-R-4,5-seco-A 0H 4gonene-3,5-dione of the formula \C/ and \C=0 R 7/ no A A further objectof the present invention is the development of a process for theobtention of 13B-R-4,5-seco-A gonene-3,5-diones of the formula 1 keta 0wherein R and A have the above-assigned meanings, by the action of ahydrolyzing acid, and (e) recovering said 13fi-R-4,5-seco-A-gonene-3,S-diones.

These and other objects of the invention will become 0 more apparent asthe description thereof proceeds.

wherein R represents an alkyl having 1 to 4 carbon DESCRIPTION OF THEENTION atoms and A represents a member selected from the group Theinvention relates to F- -8 consisting of dlones 0f the Formula I whichcomprises the steps of (a) causing the double bond to migrate from the9,10 position to the 9,11 position of 0 a 3-ketal of a 13pR-4,5-seco-A-gonene-3,S-dione of the 7 formula wherein, here and in the following, Rrepresents an alkyl having 1 to 4 carbon atoms, either branched orstraight chain, Y represents a hydroxyl and Z represents a hydrogen or Zand Y together represent a ketonic oxygen.

The compounds of the General Formula I are useful as intermediates forthe synthesis of steroids and steroidal derivatives. There use insteroid synthesis allows the btention in an advantageous fashion ofnumerous known steroids and steroidal derivatives having usefulphysiological properties by an unobvious new method of synthesis.

The new compounds of the General Formula I are thus useful asintermediates in the synthesis of diverse steroidal compounds such asthe l3;3R-A -gonene-115,17/3-diol-3- ones, the 13fl-R-A-gonadiene-11}9,17fi-diol-3-ones, the 13,8 R A-g0nadiene-l1B-0l-3,l7-di0nes, the 13j8-R- A -gonatriene-175-ol-3-onesand other steroidal derivatives of known interest.

The process for the preparation of the compounds of the General FormulaI is illustrated by the following flow diagram of Table I.

TABLE I (III) This process is characterized essentially in the followingsteps.

4 (l) The double bond in the 9,10 position of a S-ketal of a is reducedby the action of a reducing agent.

(4) The S-ketal of a Y 1113-hydroxy-13B-R-17 -4, 5-seco-A-gonene-3,5-dione, V

formed, is subjected to an acid hydrolysis.

(5) The desired corresponding Y -1247 4, fi-seco-N-gonene-l16-01-3,5-dlono, I

is recovered.

The process of the invention can be further characterized by the methodsof execution indicated below.

The basic isomerization agent utilized in step 1 to act on the 3-ketalof a Y IBfl-R-IZ -4, 5-seoo-A-gonene-3, 5-dlone, II

is a strong base such as an alkali metal tertiary-loweralkanolate, analkali metal amide or an alkali metal acetylide, preferably a potassiumtert.-amylate or tert.-butylate. The isomerization in a basic media ofthe Y 3-ketal of :1 13 3-11-17 -4, 5-seco-A-gonene-3,5-dlone, II

is effected conveniently in the presence of an organic solvent such asdimethylsulfoxide, dimethylformamide or the dimethyl ether ofdiethyleneglycol, at about room temperatures. The isomerization step isfollowed by the action of an acid agent, preferably an organic acid suchas a lower alkanoic acid, for example, acetic acid, or boric acid. Theacid agent is utilized in an aqueous solution, and the reaction media ispreferably kept weakly alkaline.

The basic media in which the 3-ketal of a is oxidized, is selectedparticularly from the group consisting of the aliphatic tertiary amines,preferably the trilower alkylamines such as triethylamine; the cyclictertiary amines such as pyridine and its homologs; and the organicderivatives of quaternary ammonium such as the benzyl-tri-lower-alkylammonium halides, for example,

benzyltrimethyl ammonium chloride. The oxidization of the 3-ketal of a Y13541-17 -4, 5-seco-A -gonene-3, 5-dlone, III

by a gas containing oxygen is effected conveniently in the presence of alower alkanol such as ethanol or methanol or in the presence of anN,N-di-lower-alkyl lower-alkanoylamide such as dimethylformamide, orin.a mixture of these, at about room temperature.

In order to effect the reduction of the 3-ketal of an Y11B-hydroperoxy-13B-R-l7 4, 5-seco-A-gonene-3, 5-one, IV

preferably a phosphite is chosen as the reducing agent, such as atri-lower-alkyl phosphite, for example, trimethylphosphite ortriethylphosphite. An alkali metal iodide such as potassium iodide, inthe presence of a lower alkanoic acid, such as acetic acid, can also beutilized, or also other reducing agents can be utilized. The reductionreaction is preferably conducted in the presence of the solvent utilizedin the preceding oxidization step at temperatures up to the refluxtemperature. Preferably the excess of the reducing agent is destroyed byan oxidizing agent such as hydrogen peroxide before the resultantcompound is recovered.

The acid utilized in the acid hydrolysis step in obtain the hydrolysisof the 3-keta1 of an is an organic carboxylic acid such as a loweralkanoic acid, for example, acetic acid or a hydroxy-lower-alkanoicacid, for example, citric acid. The acid hydrolysis step is convenientlyeffected in the presence of one or several organic solvents such as alower alkanol, for example, methanol or ethanol, or an aromatichydrocarbon solvent such as benzene or toluene. Small amounts of waterare conveniently utilized and the hydrolysis is conducted at elevatedtemperatures up to the reflux temperature.

As starting materials, the 3-ketal of a /Y 13 8-12-17-4,5-seco-A-gonene-3,5-dione is preferably a 3-1ower alkylenedioxy ketalsuch as 3,3- ethylenedioxy. The 3,3-ethylenedioxy-13p-R-4,5-seco-Agonene-lZB-ol-S-ones (II, with order to ketal= C HzO Y=OH, Z=H) can beobtained according to the process of the US. Pat. 3,413,314. The3,3-ethylenedioxy-13p-R- gonene-17,B-ol--ones (II, with CHr-O ketal=Y+Z=O) are obtained particularly by the action of an oxidizing agent onthe corresponding 3,3-ethylenedioxy- 13B-R-4,5-seco-A-gonene-l7fl-ol-5-ones.

As has been mentioned above, the new compounds of the General Formula Iare useful as intermediates in the synthesis of diverse monoenic, dienicor trienic steroid derivatievs and other steroids of known interest.

Several of such applications are given below as well as in the examples.

(A) A process for the preparation of 13B-R-A -gonene- 113,17p-diol-3-ones was realized as follows:

l3B-R-4,5-seco-A -gonene-11/3,17fi-diol-3,5-dione is subjected to acatalytic hydrogenation, then the resultant 13,3-R-4,5-seco-gonane-1lfi,l7;3-diol-3,5-dione is cyclized by the action ofan acidic or basic cyclization agent. The corresponding 13fl-R-A-gonene-11,8,17fi-diol-3-one is obtained. The catalytic hydrogenation isconveniently effected with the aid of palladium hydroxide.

This catalytic hydrogenation supplies, in addition to 13/8-R-4,5-seco-(9a,l0/3) gonane 115,175 diol 3,5-dione, another isomer, the13,3 R 4,5 seco-(9/3,l0u)-gonane- 1l/3,17fi-diol-3,5-dione. The twoisomers are separated due to their differences of solubility in asolvent or a mixture of solvents conveniently chosen, or bychromatography.

The basic agent utilized in order to effect the cyclization of the 133-R-4,5-seco-gonane-1lfl,l7p-diol-3,5-dione is, for example, an alkalimetal hydroxide such as sodium or potassium hydroxide while operating inthe presence of a lower alkanol such as methanol. The acidic agentutilized, if desired, in order to effect the same cyclization is, forexample, hydrochloric acid, while operating in an acetic acid media.

(13') A process for the preparation of the l3fi-R-Agonadiene-l13,175-diol-3-ones and the 13,6-R-Agonatriene-3,11fl,l7p-triols was realized as follows:

l3fl-R-4,5-seco-A -gonene-1lfl,l7fl-diol-3,5-dione is cyclized by theaction of a basic isomerization agent. The resultant 13 LR A gonadiene115,175 diol-3-one, is isomerized, if desired, by heating in thepresence of a catalyst to obtain the corresponding 13fi-R-A-gonatriene-3,1 1 (i, 17,3-triol.

The basic agent utilized in order to effect the cyclization of the13fl-R-4,5-seco-A -gonene 11 8,17,? diol-3,5- dione is, for example, analkali metal hydroxide, such as sodium or potassium, while operating ina lower alkanol such as methanol.

The isomerization catalyst utilized in order to effect isomerization ofthe 13p-R-A -gonadiene-11 3,17B-diol-3- one is particularly palladiumhydroxide. This isomerization is conveniently elfected by heating in alower alkanol in the presence of a weak base such as magnesia.

(C) A process for the preparation of the Y 13fl-R-17 -A--"-gonatriene-3-ones was realized as follows:

Y llfi-hydroxy-Bfl-R-Hf -4,5-seeo-A'-gonene-3,5-dione is cyclized in abasic media. The resultant Y 13,8-R-17 -A --gonadiene-115-ol-3-one isdehydrated by the action of an acidic agent. The corresponding /Y1318-11-17 -A gonatrlene-3-one is obtained.

The basic agent utilized in order to efiect the cyclization of the is,for example, an alkali metal hydroxide, such as sodium or potassiumhydroxide, while operating in a lower alkanol, such as methanol.

The acidic agent utilized in order to effect the dehydration of theresultant is a strong acid, preferably a strong mineral acid such asperchloric acid, in solution in an organic solvent or mixture of organicsolvents, such as methylene chloride and acetonitrile. The dehydratingagent can also be concentrated sulfuric acid and, then, this dehydrationis effected in the presence of an organic solvent, such as methylenechloride or ether, in a short time of the order of 3 to 15 minutes andat a temperature between C. and 10 C.

The following examples are illustrative of the practice of the inventionwithout, however, being deemed limitative in any manner.

EXAMPLE 1 4,5 -seco-A -estrene-1 1 p, 1 7B-diol-3,5-dione Step A:3,3-ethylenedioxy-4,5-seco-A estrene-17,6- ol-5-one.-15 gm. of3,3-ethylenedioxy 4,5 seco A estrene-17i3-ol-5-one (product obtained bythe application of the process of US. Pat. No. 3,413,314), then gm. ofpotassium tert.-butylate were introduced under an inert atmosphere, inthe absence of light, into 75 cc. of dimethylsulfoxide. The reactionmixture was agitated at room temperature for a period of 5 hours, thenthe reaction mixture was poured into a mixture of 600 cc. of a 3%aqueous solution of boric acid and ice. The pH of the reaction media wasabout 8.5. The precipitate formed was extracted with methylene chloride.The methylene chloride solution was washed with water, dried, andconcentrated to dryness. 16.2 gm. of raw 3,3-ethylenedioxy- 4,5-seco-A-estrene-l7p-ol-5-one was obtained, which was utilized as such for thenext step.

As far as is known, this compound is not described in the literature.

Step B: 3,3-ethylenedioxy-1lfl-hydroperoxy 4,5 seco- A-estrene-l7,6-ol-5-one.l6.2 gm. of raw 3,3-ethylenedioxy-4,5-seco-A-estrene-17,8-01-5 one were dissolved in 150 cc. of ethanol containing1% of triethylamine. The solution was agitated under an atmosphere ofoxygen at room temperature during 24 hours. It absorbed about 500 cc. ofoxygen. The 3,3-ethylenedioxy-l1p hydroperoxy- 4,5-seco-A-estrene-l75-ol-5-one thus obtained was utilized as such in solution forthe next stage.

As far as is known, this compound is not described in the literature.

Step C: 3,3-ethylenedioxy-4,5-seco-A -estrene 1113,1713- diol-5-one.6.6cc. of triethyl phosphite were introduced into the solution of3,3-ethylenedioxy-1lp-hydroperoxy- 4,5-seco-A -estrene-17 3-ol-5-oneobtained in the preceding step (and derived from 15 gm. of3,3-ethylenedioxy-4,5- seco-A -estrene-17p-ol-5 one). The reactionmixture was heated to reflux and maintained there for a period of onehour. Then the reaction mixture was poured into a mixture of 30 cc. of a30% aqueous solution of hydrogen peroxide, of ice and of water. Themixture was agitated; then the aqueous phase was extracted withmethylene chloride. The methylene chloride extracts were washed withwater and dried. Thereafter, the dried extracts were treated with animalcarbon black, agitated, and the carbon black was eliminated byfiltration. Then the organic solution was concentrated to dryness. 19gm. of raw 3,3- ethylenedioxy-4,5-seco-A -estrene-1 15,17fi-diol-5-onewere obtained, which was utilized as such for the next step.

As far as is known, this compound is not described in the literature.

Step D: 4,5-seco-A -estrene-11p,l7fi-diol 3,5-dione. 9.5 cc. of water,9.5 cc. of citric acid, then 19 gm. of raw 3,3-ethylenedioxy-4,5-seco-A-estrene-11 8,17;3-diol-5 one (derived from 15 gm. of 3,3-ethylenedioxy4,5 seco- A -estrene-17fi-ol-5-one) were introduced into 150 cc. ofbenzene under an atmosphere of nitrogen. The reaction mixture was heatedto reflux and maintained there for a period of one hour. Thereafter, thereaction mixture was cooled and made alkaline by the addition of anaqueous solution of sodium bicarbonate. The organic phase was separatedby decantation. The aqueous phase was extracted with methylene chloride.The organic phases were combined, washed with water and dried. Animalcarbon black was added to the dried organic phases, and the mixture wasagitated. The carbon black was eliminated by filtration and the solutionwas concentrated to dryness. The residue was dissolved in methylenechloride. The methylene chloride solution was passed through a column ofmagnesium silicate, and the solution obtained was concentrated todryness. The residue was crystallized from ethyl acetate. 4.7 gm. of4,5-seco-A estrene 1118,1713- diol-3,5-dione were obtained, having amelting point of 133 C. and a specific rotation [a] =-{-66 (c.=0.5% inmethanol).

On concentration to dryness of the mother liquors from thecrystallization step, then by purification by crystallization fromisopropyl ether, 1.62 gm. of a second yield was obtained having amelting point of 133 C. Analysis.--C -H O molecular weight=306.39:Calculated (percent): C, 70.56; H, 8.5. 'Found (percent): C,

Ultraviolet spectra (ethanol):

As far as is known, this compound is not described in the literature.

Max. at 246 mu (e EXAMPLE 2 13fi-ethyl-4,5-seco-A -gonene-1l/3,178-diol-3,5-dione Step A: 3,3-ethylenedioxy-13fi-ethyl-4,5 seco Agonene-17fi-ol-5-one.4 gm. of 3,3-ethylenedioxy-l3flethyl-4,5-seco-A-gonene-17fl-ol-5 one, having a melting point of to C. (product obtainedby the application of the process described in US. Pat. No. 3,413,314),were dissolved in cc. of dimethylsulfoxide under an atmosphere ofnitrogen. 32 gm. of potassium tert.-butylate were added to the solution,and the reaction mixture was agitated for a period of 5 hours at roomtemperature. The reaction solution was then poured into a mixture of iceand 1,200 cc. of a 3% aqueous solution of boric acid. The reactionmixture was agitated, then the aqueous phase was extracted withmethylene chloride. The combined methylene chloride extracts were washedwith water, dried, and concentrated to dryness under reduced pressure.4.15 gm. of 3,3-ethylenedioxy-13fl-ethyl-4,5 -seco- A-gonene-17fi-ol-5-one were obtained, having a specific rotation [a]=0i1.5 (c.=0.5% in methanol containing 1% of pyridine). The product wasutilized as such for the following step.

Ultraviolet spectra (ethanol):

max. at 246 my. (e=1,497) inflection at 285 mu (6:278)

As far as is known, this compound is not described in the literature.

Step B: 3,3-ethylenedioxy-1lfi-hydroperoxy-l3B-ethyl- 4,5-seco-A-gonene-17y8-o1-5-one.4 gm. of 3,3-ethylenedioxy-13fl-ethyl-4,5-seco-A-gonene-l7fi-ol-5-one (derived from 3.85 gm. of3,3-ethylenedioxy-13fi-ethyl-4,5- seco-A -gonene-17,9-ol-5-one) weredissolved in 40 cc. of ethanol containing 1% of triethylamine. Thesolution was then agitated in an atmosphere of oxygen for 15 hours atroom temperature. About 230 cc. of oxygen were thus absorbed. The3,3-ethylenedioxy-1lp-hydroperoxy-Bfiethyl-4,5-seco-A-gonene-l78-ol-5-one thus obtained was utilized as such in solution for the nextstep.

As far as is known, this compound is not described in the literature.

Step C: 3,3-ethylenedioxy-13B-ethyl-4,5-seco-A-gonene-l1/3,17;8-diol-5-one.2.4 cc. of triethyl phosphite wereintroduced into the solution of 3,3-ethylenedioxy- 11/3 hydroperoxy13B-ethyl-4,5-seco-A gonene-17/3-ol- 5-one (derived from 3.85 gm. of3,3-ethylenedioxy-13B- ethyl-4,5-seco-A -gonene-17p-ol-5-one). Thereaction mixture was agitated for one hour at room temperature.Thereafter, the mixture was poured into a mixture of a 30% aqueoussolution of hydrogen peroxide, and of ice, and agitated. The aqueousphase was extracted with methylene chloride. The combined methylenechloride extracts were washed with water and dried. Animal carbon blackwas added to the methylene chloride solution, which was agitated,Thereafter, the carbon black was eliminated 'by filtration, and thesolution was concentrated to dryness. The residue obtained was purifiedby chromatography through silica gel. The elution of the column waseffected by a mixture of cyclohexane, 95% ethanol, and ether. Afterelimination of a mobile fraction which did not contain the desiredllfi-hydroxylate derivative, there was separated successively aheterogeneous fraction (A); a fraction (B) of 2.77 gm. of raw3,3-ethylenedioxy-13fi-ethyl 4,5-seco-A -gonene-l15,175- diol-S-one,having a specific rotation [a] +70 (c.= 0.5% in methanol); then aheterogeneous fraction (C).

Fraction (B) was utilized as such for the following step. The fractions(A) and (C), comprised of 3,3-ethylenedioxy 13B ethyl 4,5 seco-A-gonene-l1,3,l7/3-diol- 5-one mixed with impurities, were subjected tocitric acid hydrolysis according to the following step and furnished,with lower yields than those for the fraction (B),

13 fl-ethyl-4,5 -seco-A -gonene-1 1 8, 17B-diol-3,5-dione.

As far as is known, 3,3-ethylenedioxy-l3fl-ethyl-4,5- seco-A-gonene-1113,17fi-diol-5-one is not described in the literature.

Step D: l3fl-ethyl-4,5-seco-A -gonene-11/3,17,3-diol-3,5- dione.-1.4 cc.of water, 1.4 gm. of citric acid, and then 2.45 gm. of3,3-ethylenedioxy-l3 3-ethyl-4,5-seco-A -gonene-l lfi,17B-diol-5-one,the fraction (B) obtained in the preceding step, were introduced into 20cc. of benzene in an atmosphere of nitrogen. The reaction mixture washeated to reflux and maintained at reflux for a period of one hour.Thereafter the reaction mixture was cooled, and water was added to itwith agitation. The organic phase was separated by decantation. Theaqueous phase was extracted with methylene chloride. The organic phaseswere combined, washed with water, with an aqueous solution of sodiumbicarbonate, and then with water. The organic solution was then dried,and animal carbon black was eliminated by filtration, and the organicsolution was concentrated to dryness. The residue was crystallized froma mixture of methylene chloride and isopropyl ether. 1.33 gm. of13fi-ethyl-4,5-seco-A -gonene- 11p,17 S-diol-3,5-dione were obtained,having a melting point of 159 C. and a specific rotation [a] '-=+52.5

(c.=0.5% in methanol).

By hydrolysis in a citric acid media according to the same operatorymethod described above, the fractions (A) and (C) obtained in thepreceding step gave 0.200 gm. of 13/3 ethyl 4,5-seco-A -gonene11B,17-diol-3,5- dione, having a melting point of 157 C.

Analysis.C H D molecular weight=320.4l; Calculated (percent): C, 71.22;H, 8.807. Found (percent): C, 71.0; H, 8.6.

Ultraviolet spectra (ethanol): max. at 247 m (6:

M.N.R. spectra (deutero chloroform):

signal at about 72 mhz. (multiplet) corresponding to hydrogens of the CHgroup of the ethyl in the 13 position signal at 125 mhz. correspondingto hydrogens of the COCH group 1'0 signals at 216.5, 224, and 232 mhz.(triplet) corresponding to the hydrogen in the 17 position.

As far as is known, 13fl-ethyl-4,5-seco-A -gonene-11,8,-17,B-diol-3,5-dione is not described in the literature.

EXAMPLE 3 4,5-seco-A -estrene-1 lfl-ol-3,S,17-trione Step A:3,3-ethylenedioxy-4,5-seco-A -estrene-5,17- dione.-l0 gm. of3,3-ethylenedioxy-4,5-seco-A -estrene- 1718-ol-5-one (product obtainedby the application of the process of US. Pat. 3,413,314) were introducedinto 100 cc. of acetone, and the mixture was agitated at roomtemperature until dissolution occurred. Therefore, the reaction mixturewas cooled to 10 C., and 7.8 cc. of a 4.6 N solution of a sulfochromicacid mixture was added. The suspension obtained was agitated for onehour at 10 C., then poured into 300 cc. of a saturated solution ofsodium bicarbonate and 500 cc. of water. The insoluble material wasfiltered, and the aqueous phase was extracted with methylene chloride.The organic phase was washed with water, dried, and evaporated todryness under vacuum. 9.4 gm. of 3,3-ethylenedioxy-4,5-seco-Aestrene-5,17-dione were obtained, which was utilized as such for thenext step of the synthesis. This product had a specific rotation [a]=+44.5i2 (c.=0.5% in methanol).

As far as is known, this compound is not described in the literature.

Step B: 3,3-ethylenedioxy-4,5-seco-A -estrene-5,17- dione.-91.5 gm. of3,3 ethylenedioxy 4,5 seco A estrene-5,l7-dione and gm. of potassiumtert.-butylate were introduced, under an inert atmosphere, into 460 cc.of dimethylsulfoxide. Next, the reaction mixture was agitated at roomtemperature for 5 hours, then poured into a mixture of 3.66 liters ofwater and ice and 3.66 liters of a 3% aqueous solution of boric acid.The precipitate formed was extracted with methylene chloride. Themethylene chloride solution was washed with water and dried. 2.35 litersof a solution of 3,3-ethylenedioxy-4,5- seco-A -estrene-5,17-dione inmethylene chloride were obtained, which solution was utilized as suchfor the next step of the synthesis.

Ultraviolet spectra (ethanol): A max. at 246 mu iZim As far as is known,this compound is not described in the literature.

Step C: 3,3-ethylenedioxy-1lfi-hydroperoxy-4,5-seco- A-estrene-5,17-dione.-915 cc. of ethanol containing 1% of triethylaminewere added to the solution obtained from the preceding step. A stream ofoxygen was then passed through the solution under agitation overnight. Asolution of 3,3-ethylenedioxy 11p hydroperoxy-4,5-seco-A-estrene-5,l7-dione in methylene chloride was obtained, which wasutilized as such for the next step.

As far as is known, this compound is not described in the literature.

Step D: 3,3-ethylenedioxy-4,5-seco-A-estrene-113-01- 5,17-dione.-Thesolution of 3,3-ethylenedioxy-llB-hydroperoxy-4,5-seco-A-estrene-5,17-dione obtained in the preceding step was heated underagitation and in an atmosphere of nitrogen, to the point wheredistillation of methylene chloride commenced. Then 47.5 cc. of triethylphosphite were introduced into the warm mixture. The heating wascontinued for a period of one hour. Thereafter, the mixture was cooledto room temperature and poured into a mixture of 2.65 liters of waterand ice and 392 cc. of a 30% hydrogen peroxide solution. Agitation ofthe mixture was maintained for a period of 45 minutes at roomtemperature. Thereafter, the organic phase was decanted. The aqueousphase was extracted with methylene chloride. The combined methylenechloride extracts were washed with water, dried, and distilled todryness under vacuum. 96 gm. of 3,3-ethylenedioxy-4,5-seco-Aestrene-llfl-ol-5,l7-dione were obtained which were utilized as such forthe following step.

As far as is known, this compound is not described in the literature.

Step E: 4,5-seco-A -estrene-11p-ol-3,5,l7-trione.96 gm. of3,3-ethylenedioxy-4,5-secQ-A -estrene-ll pol-5,17- dione were introducedinto 960 cc. of benzene. Then 96 cc. of water and 96 cc. of citric acidwere added to the mixture under agitation and under an atmosphere ofnitrogen. The reaction mixture was heated to reflux for a period of onehour, cooled, and the aqueous phase was decanted. The aqueous phase wasextracted with benzene. The organic phases were combined, and washedwith a saturated solution of sodium bicarbonate, and then with wateruntil the wash waters were neutral. The organic solution was dried andfiltered under vacuum. The filtration residue was washed with benzene,and the combined filtrates were distilled to dryness under vacuum. 74.5gm. of 4,5-seco-A -estrene-l1fi-ol-3,5,17-trione were obtained.

As far as is known, this compound is not described in the literature.

EXAMPLE 4 1313-ethyl-4,5-seco-A -gonene-1lp-ol-3,5,l7-trione Step A:3,3-ethylenedioxy 13ft ethyl-4,5-seco-A gonene-5,17-dione.5 gm. of3,3-ethylenedioxy-l3flethyl-4,5seco-M-gonene-17fl-ol-5-one (a productobtained by the application of the process of US. Pat. No. 3,413,314)were introduced under an atmosphere of nitrogen into 50 cc. of acetone.The mixture was cooled to C. and, over a period of about 10 minutes, 39cc. of a 4.6 N solution of a sulfochromic acid mixture was addedthereto. The reaction mixture was agitated for one hour at +10 C., thenpoured into a mixture of 150 cc. of a 10% aqueous sodium bicarbonatesolution and 250 cc. of iced water. The insoluble material was filtered.The aqueous phase was extracted with methylene chloride. The organicphases were combined, washed with water, dried, and evaporated todryness. 4.6 gm. of 3,3- ethylenedioxy-13fi-ethyl 4,5 seco-A-gonene-5,17-dione 'were obtained, which were utilized as such for thenext step.

Ultraviolet spectra (ethanol): x max. at 249 m As far as is known, thiscompound is not described in the literature.

Step B: 3,3 ethylenedioxy-l3 8-ethyl-4,5-seco-A gonene-5,17-dione.29.5gm. of 3,3-ethylenedioxy-l3flethyl-4,5-seco-A -gonene-5,17-dione, then27 gm. of potassium tert.-butylate were introduced under an inertatmosphere into 270 cc. of dimethylsulfoxide. The mixture was agitatedat room temperature for 5 hours and then poured into a mixture of 1,080cc. of water and ice and 1,080 cc. of a 3% boric acid solution. Themixture was agitated for minutes and extracted with methylene chloride.The organic phase was washed with water and dried. 2.3 liters of asolution of 3,3-ethylene-dioxy-13flethyl-4,5-seco-A -gonene-S,17-dionein methylene chloride were obtained, which solution was utilized as suchfor the following step.

As far as is known, this compound is not described in the literature.

Step C: 3,3-ethylenedioxy-llfi-hydroperoxy-l3B-ethyl- 4,5-seco-A-gonene-5,l7-dione.270 cc. of ethanol containing 1% of triethylaminewere added to the solution obtained in the preceding step. Then a streamof oxygen was passed through the reaction mixture under agitationovernight. A solution of3,3-ethylenedioxy-1lfl-hydroperoxy-l3/8-ethyl-4,5-seco-A-gonene-5,17-dione was obtained, which was utilized as such for thefollowing step.

As far as is known, this compound is not described in the literature.

Step D: 3,3-ethylenedioxy-13,8-ethyl 4,5 seco-Agonene-l1fi-ol-5,17-dione.--The solution of3,3-ethylenedioxy-l1fl-hydroperoxy-13B-ethyl 4,5 seco-A -gonene-5,17-dione was heated under agitation and under an atmosphere ofnitrogen, until distillation commenced. Then 9 cc. of triethyl phosphitewere added thereto. The methylene chloride was distilled. Then thereaction mixture was heated to reflux for a period of one hour underagitation. The mixture was cooled to room temperature, then poured intoa mixture of 1.5 liters of water and ice and 50 cc. of a 30% hydrogenperoxide solution. The mixture was agitated for 15 minutes. Then theaqueous phase was extracted with methylene chloride. The organic phaseswere washed with water, then dried. The solution was distilled todryness.

34 gm. of 3,3,ethylenedioxy-13B-ethyl-4,5-seco-A -gonene-llfi-ol-5,17-dione were obtained, which product was soluble in the usualorganic solvents and insoluble in water.

As far as is known, this compound is not described in the literature.

Step E: l3fl-ethyl-4,5-seco-A -gonene-l1fi-ol-3,5,17-trione.-34 gm. of3,3-ethylenedioxy-13{3-ethyl-4,5-seco-A gonene-l 1B-o1-5,17-dione, 27gm. of citric acid, and 27 cc. of water were introduced under anatmosphere of nitrogen into 270 cc. of benzene. The mixture was heatedto reflux for a period of one hour and thereafter cooled to roomtemperature. 600 cc. of a saturated aqueous solution of sodiumbicarbonate were added thereto and the aqueous phase was decanted. Theaqueous phase was extracted with methylene chloride. The organic phaseswere combined, washed with water until the wash water was neutral,dried, and concentrated to dryness under vacuum. 300 gm. of13fi-ethyl-4,5-seco-A -gonene-llB-ol-3,5,l7-trione were obtained.

Ultraviolet spectra (ethanol): A max. at 244mg l'Z.= As far as in known,this compound is not described in the literature.

Examples of utilization of the compounds of Formula I:

EXAMPLE 5 A -estrene-1 l 5,17fi-diol-3-one Step A: 4,5 seco-estrane-l l3,l7,e-diol-3,5-dione.--A mixture of 522 cc. of ethanol containing 5% ofwater and 52.2 cc. of triethylamine was introduced into a hydrogenationapparatus. Then 52.2 gm. of 4,5-seco-A -estrene-11/3,17;3-diol-3,5-dione (the product obtained in Step D of Example 1),some animal carbon black, and 2.6 cc. of a solution of palladiumhydroxide in aqueous hydrochloric acid (the solution analyzing 10 gm. ofpalladium per cc.) were thereafter introduced under an atmosphere ofnitrogen into the hydrogenation apparatus. The apparatus was purged andagitated under an atmosphere of hydrogen until the end of the hydrogenabsorption. 3.9 liters of hydrogen were thus absorbed. The catalyst andthe carbon black were eliminated by filtration. The filtrate wasconcentrated to dryness under reduced pressure.

The product obtained (58 gm.) was dissolved at reflux in 580 cc. ofethyl acetate. The solution was cooled and crystallization was initiatedby scratching. The mixture was cooled to 0 C. The precipitate formed wasisolated by vacuum filtering and drying. 7 gm. (product A) of raw(9fl,l0a)4,5-seco-estrane-l1p,l7;3-diol-3,5-dione was thus obtained.

The filtrate was concentrated to dryness under reduced pressure. 50.5gm. of raw 4,5-sec-estrane-1 1B,17fl-diol-3,5- dione were obtained,which was utilized as such for the next stage.

By crystallization from ethyl acetate, 4,5-seco-estrane-1lB,17B-diol-3,5-dione was obtained, having a melting point of 129 C.and a specific rotation [a] =+25 (c.=0.5% in methanol).

13 Analysis.-C H O molecular weight=308.39: Calculated (percent): C,70.09; H, 9.15. Found (percent): C, 70.1; H, 8.8. Circular dichroism(dioxane):

max. at 290 m (Ae=3.l) inflection towards 297 mp M.N.R. spectra (deuterochloroform): the spectra was composed as follows:

signal at 64.5 mhz. corresponding to hydrogens of the methyl in the 13position signal at 127 mhz. corresponding to hydrogens of the methyl ofthe --COCH group signal at 219 mhz. corresponding to the hydrogen in the17 position signal at 256 mhz. corresponding to the hydrogen in the 11position.

As far as is known, this compound is not described in the literature.

Step B: A -estrene-11,3,l7B-diol-3-one.50.5 gm. of raw4,5-seco-estrane-1lfi,l7fl-diol-3,5-dione, obtained in Step A, wasintroduced under an atmosphere of nitrogen into 1010 cc. of a methanolicsolution of potassium hydroxide containing 0.45 gm. of potassiumhydroxide per 100 cc. The reaction mixture was heated to reflux andmaintained at reflux for a period of 2 hours. Thereafter, the mixturewas cooled to 20 C. and acidified to a pH of 5.5 by the addition ofacetic acid. Water was added to the reaction mixture, and the methanolwas eliminated by distillation under reduced pressure. The precipitateformed was vacuum filtered and dried. Thereafter, the residue wascrystallized from ethyl acetate and 26.6 gm. of A-estrene-11B,17fi-diol-3-one were obtained, having a melting point of220 C. By concentration of the mother liquors from the crystallizationstep, a second yield of 3.26 gm. was isolated, having a melting point of219 C.

A sample of the first yield, having a melting point of 220 C., waspurified by chromatography through silica gel. The product obtained hadthe following characteristics:

Melting point =222 C.

Analysis.-C H O molecular weight=290.40: Calculated (percent): C, 74.44;H, 9.02. Found (percent):

Circular dichroism (dioxane):

max. at 342 m (Ae=-1.13) max. at 329 III/1. (Ae=-l.397) max. at 318 m,(Ae=-1.107) max. at 233 III/l. (Ae=+4.89)

This product is identical to that described in US. Pat. No. 2,778,841.

EXAMPLE 6 (9;3,10a)-A -estrene-11fi,17,6-diol-3-one Analysis.-C H Omolecular weight==308.40: Calculated (percent): C, 70.10; H, 9.15. Found(percent): 69.8; H, 9.2.

Circular dichroism (dioxane): max. at 292 mp. (As:

As far as is known, this compound is not described in the literature.

Step B: (95,1000 -A -estrene-11,8,17,8-diol-3-one-5 gm. of (93,1000 4,5seco-estrane llfl,l7fl-diol-3,5-dione were introduced under anatmosphere of nitrogen into 100 cc. of a methanolic solution ofpotassium hydroxide containing 0.45 gm. of potassium hydroxide per cc.The solution was heated to reflux and maintained there for a period of 2hours. The reaction solution was then cooled to 20 C. and brought to apH of 5.5 by the addition of acetic acid. Water was then added thereto,and the methanol was eliminated by distillation under reduced pressure.The precipitate formed was vacuum filtered and dried. Thereafter it wasdissolved in 40 volumes of ethyl acetate, filtered, and cooled to 0 C.The precipitate formed was isolated by vacuum filtration and dried. 3.28gm. of (9fl,10a)-A4-estrene 11,19,175 diol-3-one were obtained, having amelting point of 272 C. and a specific rotation [11], 75.5 (c.=0.6% inmethanol).

Analysis.C H O molecular weight=290.4; Calculated (percent): C, 74.44;H, 9.03. Found (percent): C, 74.4; H, 9.0. Circular dichroism (dioxane):

max. at 359 m (A,-=-+0.174)

max. at 344 mu (A,=+0.700)

max. at 330 m (Y,=+0.97)

max. at 318 mp (A =+0.83)

inflection towards 308 mp.

max. at 234 m (A: --9.8)

inflection towards 240 and 225 my.

This compound can be used in steroid synthesis according to French Pat.1,404,412.

EXAMPLE 17 13p-ethyl-A -gonene-115,17fl-diol-3-one Step A:13fi-ethyl-4,S-seco-gonane-11,B,17fi-diol-3,5-dione.A mixture of 180 cc.of ethanol and 18 cc. of triethylamine were introduced into ahydrogenation apparatus. Then under an atmosphere of nitrogen, 9 gm. of1319 ethyl 4,5-seco A gonene-l1B,l7fl-diol-3,5-dione (product obtainedin Step D of Example 2), some animal carbon black, and 0.45 cc. of asolution of palladium hydroxide in aqueous hydrochloric acid (solutioncontaining 10 gm. of palladium per 100 cc.) were introduced into thehydrogenation apparatus under an atmosphere of nitrogen. Thehydrogenation apparatus was purged, and the contents were agitated underan atmosphere of hydrogen until the end of the absorption of thehydrogen. The agitation was continued under an atmosphere of hydrogenfor another hour. The apparatus was opened and the contents removedtherefrom. The catalyst and the carbon black were removed from thereaction mixture by filtration. The filtrate was concentrated to drynessunder reduced pressure. The residue was crystallized from ethyl acetateand 3.82 gm. of 13fl-ethyl-4,5-seco-gonane-11fl,17fl-diol-3,5- dionewere obtained, having a melting point of 173 C.

A sample of this product was crystallized from ethyl acetate to give aproduct having a melting point of 173 C. and a specific rotation [a]=+21 (c.=0.5% in methanol).

Analysis.C H O molecular weight=322.43; Calculated (percent): C, 70.77;H, 9.38. Found (percent): C, 70.7; H, 9.4.

Circular dichroism: A, at 290 m =3.44.

As far as is known, this compound is not described in the literature.

Step B: 13B-ethyl-A -gonene-l1fl,17fl-diol-3-one.3.8 gm. of13B-ethyl-4,5-seco-gonane-11 8,17[3-diol-3,5-dione were introduced into76 cc. of a methanolic solution of potassium hydroxide containing 0.5gm. of potassium hydroxide per 100 cc. under an atmosphere of nitrogen.The mixture was heated to reflux, and the reflux was maintained for aperiod of 2 hours. Thereafter, the reaction mixture was cooled andacidified by the addition of a dilute aqueous solution of acetic acid.The methanol was eliminated by distillation under reduced pressure, andthe reaction mixture was cooled. The crystals ob- 15 tained were vacuumfiltered, washed and dried. 3.28 gm. of 13 8-ethyl Agonene-l1,3,17fi-diol-3-one were ob tained, having a melting point of213 C.

A sample of this product was recrystallized from ethyl acetate to give aproduct having a melting point of 214 C. and a specific rotation [a]=+85 (c.=0.5% in methanol).

This compound is described in British Pat. No. 1,128,- 044.

EXAMPLE 8 A -estratriene-17B-ol-3-one Step A: A-estradiene-11fi,17B-diol-3-one.--3 gm. of 4,5-seco-A -estrene 11 3,17,?diol-3,5-dione were introduced under an atmosphere of nitrogen into 30cc. of a methanolic solution of potassium hydroxide containing 0.45 gm.of potassium hydroxide per 100 cc. The reaction mixture was heated toreflux and maintained there for a period of 6 hours. Thereafter, thereaction mixture was cooled to +10 C. and neutralized by the addition ofacetic acid. The solvent was eliminated by distillation. Ethyl acetatewas added to the reaction mixture, which was then cooled to C. Theprecipitate formed was vacuum filtered, dried and recrystallized fromisopropyl ether. 2.05 gm. of A -estradiene-115,17B-diol-3-one wereobtained, having a melting point of 180 C., then 192 C. and a specificrotation [a] =+44.5 (c.=0.5% in dimethylformamide) Ultraviolet spectra(ethanol): max. at 298 m (e=19,730)

This compound is identical to that described in U.S. Pat. No. 3,282,785.

Step B: A -estratriene-17/3-ol-3-one.3 gm. of Aestradiene-l13,17B-diol-3-one were introduced in an atmosphere ofnitrogen into 60 cc. of methylene chloride. The mixture was cooled to -5C. and cc. of a B. aqueous solution of sulfuric acid, then 30 cc. ofethyl ether were introduced into the solution. The reaction mixture wasagitated vigorously for 5 minutes (starting from the moment of theintroduction of the sulfuric acid) while cooling in order to bring thetemperature to and maintaining the same at 0 C. The reaction mixture wasthen poured into a mixture of water and ice. The organic phase wasseparated by decantation. The aqueous phase was extracted with methylenechloride. The methylene chloride extracts and the principal organicphase were combined. The organic solution obtained was washed by anaqueous solution of sodium bicarbonate and then with water, dried andconcentrated to dryness. The residue was dissolved in methylenechloride. The methylene chloride solution was passed through a column ofmagnesium silicate and eluted with methylene chloride. The eluate wasconcentrated to a small volume. The residue was crystallized fromisopropyl ether. 1.73 gm. of A -estratriene-17fi-ol-3-one was obtained,having a melting point of 182 C.

Ultraviolet spectra (ethanol):

max. at 238 m, (e=5,920) inflection towards 270 m (6:3,975) max. at 342I'll/I. (e=26,175)

This compound is identical to the A -estratriene- 17fl-ol-3-one obtainedby another method according to U.S. Pat. No. 3,248,294.

Step A: 13dethyl-A -gonadiene-11,3,l7 3-diol-3-one. 3 gm. of13fi-ethyl-4,5-seco-A -gonene-11B,17B-diol-3,5- dione were introducedunder an atmosphere of nitrogen into 30 cc. of a methanolic solution ofpotassium hydroxide containing 0.46 gm. of potassium hydroxide per 100cc. The reaction mixture was heated to reflux and maintained at refluxfor a period of 6 hours. Thereafter, the reaction mixture was cooled toC. and the pH was brought to between 5 and 6 by the addition of amethanolic solution of acetic acid. Then the mixture was concentrated todryness under reduced pressure. The residue was purified by acrystallization from ethyl acetate. 2.28 gm. of 13B-ethyl-A-gonadiene-1113,175- diol-3-one were obtained, having a melting point of193 C. and a specific rotation [a] =+4.5 (c.=0.5% in methanol).

Analysis.-C H O molecular weight=302.40; Calculated (percent): C, 75.46;H, 8.67. Found (percent): C, 75.2; H, 8.9.

Ultraviolet spectra (ethanol): max. at 297-298 mp On concentration to asmall volume of the mother liquors from the crystallization step, asecond yield of 0.150 gm. was obtained, having a melting point of 189 C.

As far as known, 13fl-ethyl-A -gonadiene-11p,17fldiol-3-one is notdescribed in the literature.

Step B: 13/3-ethyl-A -gonatriene-l7B-ol-3-one.-3 gm. of L3fi-ethyl-A-gonadiene-1lfl,l7p-diol-3-one were introduced, under an atmosphere ofnitrogen and while agitating in order to homogenize the mixture andwhile maintaining the temperature of the reaction mixture at +15 C.,into a mixture of 7.5 cc. of methylene chloride and 22.5 cc. of anaqueous 66 -B. solution of sulfuric acid. At the end of 6 minutes, thereaction mixture was poured on ice. The methylene chloride phase wasseparated by decantation. The aqueous phase was extracted with methylenechloride. The methylene chloride extracts and the principal organicphase were combined. The solution obtained was washed with an aqueoussolution of sodium bicarbonate and then with water. Thereafter, theorganic phase was dried, then concentrated to dryness under reducedpressure. The residue was crystallized from isopropyl ether. 1.82 gm. of13fl-ethyl-A -gonatriene-17/3-ol-3-one were obtained, having a meltingpoint of to C. (Kofler).

Ultraviolet spectra (ethanol):

max. at 238 m (e=5,650) max. at 269-270 m (e=3,635) max. at 343 m(e=26,400)

This compound is identical to 13B-ethyl-A -gonatriene-17fi-ol-3-oneobtained by another method according to Belgian Pat. 679,368.

In an analogous fashion, 13B-R-A -gonatriene-17 6- ol-3-ones having 138-propyl or 13B-butyl groups, either straight chain or branched chain,were obtained.

EXAMPLE 1O A -estradiene-11}8-0l-3,17-dione 2.3 gm. of 4,5-seco-A-estrene-11fl-ol-3,5,17-trione were introduced into 23 cc. of amethanolic potassium hydroxide solution (4 gm. per liter). The reactionmixture was heated to reflux under agitation and under an atmosphere ofnitrogen for a period of 6 hours. Thereafter, the reaction mixture wascooled to room temperature and 1 cc. of a 10% acetic acid solution inmethanol was added thereto. The reaction mixture was distilled todryness under vacuum. The residue was dissolved in 10 cc. of benzene andsubjected to chromatography through magnesium silicate with elution withbenzene. After recrystallization from ether, 0.2 gm. of A'-estradiene-11fl-ol-3,17-dione were obtained, having a melting point of179 C. and a specific rotation [m] =+84 (c.=0.5% in chloroform).

This product is identical to that described in U.S. Pat. No. 3,282,785.

EXAMPLE 11 30 gm. of 13B-ethyl-4,5-seco-A -gonene-l1/3-o1-3,5,l7- trionewere introduced into 270 cc. of a methanolic potassium hydroxidesolution (4.9 gm. per liter). The reaction mixture was heated to refluxunder agitation and an atmosphere of nitrogen for a period of one hour.Thereafter, the reactionmixture was cooled to 20 C. and brought to a pHof between and 6 by the addition of acetic acid. Then, the reactionmixture was diluted with 500 cc. of water. The aqueous phase wasextracted with methylene chloride. The combined organic phases werewashed with water, dried, and treated with animal carbon black. Theorganic phase was then filtered under 10 vacuum, washed with methylenechloride, then distilled to dryness under vacuum. The residue wastreated with isopropyl ether and with ether, then dissolved in 120 cc.of ethyl acetate, to which 100 cc. of isopropyl ether was slowly added.The mixture was agitated for one hour at C. and filtered under vacuum.The residue was triturated with isopropyl ether and dried under vacuum.5.6 gm. of 13/3-ethyl-A -gonadiene-11fl-ol-3,17-dione were obtained,having a melting point of 158 C. and

18 wherein R represents alkyl having 1 to 4 carbon atoms and Arepresents a member selected from the group consisting of 2.13p-R-4,5-seco7A -gonene-5-one of the formula Hro 0 wherein R representsalkyl having 1 to 4 carbon atoms, R represents a member selected fromthe group consisting of hydroperoxy and hydroxy, and A represents amember selected from the group consisting of and References Cited UNITEDSTATES PATENTS 3,117,979 1/1964 Nomine et a1 260-3409 3,205,226 9/ 1965Barton 2-60239.55 3,211,746 10/1965 Brown et a1. 260-397.45 3,301,7561/1967 Joly et a1. 260397.45

DONALD G. DAUS, Primary Examiner J. H. TURNIPSEED, Assistant ExaminerUS. Cl. X.R. 260-3974, 586

